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Specific SNPs in Two Genes Linked to Idiopathic Membranous Nephropathy

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A European research consortium has identified alleles at two genetic loci that appear to be strongly linked with idiopathic membranous nephropathy, which they point out is the most common diagnosis in adults with nephrotic syndrome. Their genome-wide association studies (GWAS) involving 556 patients of British, French, and Dutch descent, found SNPs within HLA-DQA1 allele on chromosome 6p21 to be most commonly associated with the disease. However, a PLA2R1 allele at 2q24 was also found to correlate with idopathic membranous nephropathy. A SNP on this gene has, moreover, recently been identified as a major target antigen in the disease. The overall results suggest that homozygosity for both at-risk alleles could be associated with a nearly 80% odds ratio for having the disease. HLA-DQA1 is an HLA class II alphachain paralogue gene, and PLA2R1 encodes phospholipase A2 receptor 1 isoform 1, a receptor for secretory phospholipase A2.

The researchers, the majority of whom hail from the Centre for Nephrology at the Royal Free Hospital, U.K., and the Institute of Child Health in the U.K., report their findings in today’s issue of NEJM, in a paper titled, “Risk HLA-DQA1 and PLA2R1 Alleles and Idiopathic Membranous Nephropathy.” The consortium was chaired by professor Peter Mathieson, dean of the Faculty of Medicine at the University of Bristol, U.K.

The research initially involved carrying out GWAS for the three populations of patients. The French study involved 75 patients with idiopathic membranous nephropathy and 157 racially matched controls. It established a significant link with SNPs in a human leukocyte antigen (HLA)-DQA1 allele on chromosome 6. The Dutch study, involving 146 Dutch patients and 1,832 racially matched controls, also established a significant association with the HLA-DQA1 allele on chromosome 6, and a PLA2R1 allele on chromosome 2. The British GWAS involved 335 participants with idiopathic membranous nephropathy, and 349 racially matched controls. It also established a significant association with SNPs within HLA-DQA1 allele on chromosome 6 and the same SNP for the PLA2R1 allele that was highlighted in the Dutch study.

When the researchers then pooled the data, which involved the examination of 242,824 common SNPs, they found significant associations for SNP rs2187668 within HLA-DQA1 on chromosome 6 and SNP rs4664308 within PLA2R1 on chromosome 2.

They subsequently reanalyzed their data with the addition of 823 publicly available white Hap-Map controls. This increased the significance of the association with HLA-DQA1, but did reduce the significance of the association with PLA2R1, Mathieson et al., point out. There was no evidence of significant genetic associations with SNPs at other genetic loci. “It appears that the risk of idiopathic

membranous nephropathy is higher with the HLA-DQA1 allele than with the PLA2R1 allele, suggesting that the HLA-DQA1 allele might facilitate autoantibody development targeting not only PLA2R1 but also other antigens,” they suggest.

Importantly, when the combined effects of the alleles at the two loci was evaluated in terms of risk for idiopathic membranous nephropathy, the odds ratio for having the disease was almost 80% for patients who were homozygous for both. Additive increases in the odds ratio were also evident, dependent on the combination of genotypes.

“Although these findings do not establish causality, they strongly suggest that an interaction between genetic variants of immune-system proteins and glomerular components form the basis for the development of idiopathic membranous nephropathy, establishing a trigger (the immune system), a bullet (PLA2R1 autoantibodies), and a target (glomerular antigen),” the authors note. “Studies to assess sequence variations in the HLA-DQA1 and PLA2R1 regions may therefore facilitate the diagnosis of idiopathic membranous nephropathy and improve our understanding of its pathophysiology.”

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